Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/99333
標題: New antitumor anthra[2,3-b]furan-3-carboxamides: Synthesis and structure-activity relationship
作者: Tikhomirov, Alexander S
Lin, Chia-Yang
Volodina, Yulia L
Dezhenkova, Lyubov G
Tatarskiy, Victor V
Schols, Dominique
Shtil, Alexander A
Kaur, Punit
Chueh, Pin Ju
闕斌如
Shchekotikhin, Andrey E
關鍵字: Anthra[2,3-b]furan-3-carboxamides;Antiproliferative activity;Apoptosis;Multidrug resistance;Reactive oxygen species;Topoisomerase 1;р53;Amides;Animals;Anthraquinones;Antineoplastic Agents;Apoptosis;Cell Cycle Checkpoints;Cell Line, Tumor;Drug Resistance, Neoplasm;Drug Screening Assays, Antitumor;Furans;Humans;Mice;Oxidative Stress;Structure-Activity Relationship;Topoisomerase I Inhibitors
Project: European journal of medicinal chemistry, Volume 148, Page(s) 128-139.
摘要: 
Chemical modifications of the anthraquinone scaffold are aimed at optimization of this exceptionally productive class of antitumor drugs. In particular, our previously reported anthra[2,3-b]furan-3-carboxamides demonstrated a high cytotoxic potency in cell culture and in vivo. In this study, we expanded our series of anthra[2,3-b]furan-3-carboxamides by modifying the key functional groups and dissected the structure-activity relationship within this chemotype. The majority of new compounds inhibited the growth of mammalian tumor cell lines at submicromolar to low micromolar concentrations. We found that 4,11-hydroxy groups as well as the carbonyl moiety in the carboxamide fragment were critical for cytotoxicity whereas the substituent at the 2-position of anthra[2,3-b]furan was not. Importantly, the new derivatives were similarly potent against wild type cells and their variants resistant to doxorubicin due to P-glycoprotein (Pgp) expression or p53 inactivation. The most cytotoxic derivatives 6 and 9 attenuated plasmid DNA relaxation by topoisomerase 1. Finally, we demonstrated that 6 and 9 at 1 μM induced intracellular oxidative stress, accumulation in G2/M phase of the cell cycle, and apoptosis in gastric carcinoma cell lines regardless of their p53 status. These results further substantiate the potential of anthra[2,3-b]furan-3-carboxamides as antitumor drug candidates.
URI: http://hdl.handle.net/11455/99333
DOI: 10.1016/j.ejmech.2018.02.027
Appears in Collections:生物醫學研究所

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